The clubs clash for the very first time in a competitive fixture, as Champions League drop-outs host a team that cruised through Group F in the autumn.
Match preview
Given the nature of their Champions League opponents - Borussia Dortmund, Paris Saint-Germain and Newcastle United - it was not a major upset when Milan failed to progress from this season's 'Group of Death', though they had hoped to at least replicate last year's run to the final four.
Finishing third, behind Dortmund and PSG, saw the Italian giants slip down into the Europa League, in which they must overcome a tough two-legged tie to reach the last 16.
Since their exit from UEFA's top club competition, they have found some fluency in the final third - and, crucially, a clinical edge: only RB Salzburg scored fewer goals than Milan's five in the Champions League group stage, despite just four teams taking more shots.
Posting a fourth win from five games, the Rossoneri came out on top in a tussle between the last two Serie A champions on Sunday evening, when they welcomed struggling Scudetto-holders Napoli to San Siro.
Following a fightback against Frosinone that tightened their grip on third spot, Stefano Pioli's side struck midway through the first half thanks to flying full-back Theo Hernandez, and they have closed to within one point of second-placed Juventus - city rivals Inter Milan are eight points ahead.
Having scored 20 times in eight matches this year, Milan may be comfortably on course for a Champions League place via their league finish, but they now return to a competition they are yet to master: the seven-time European champions have never before won the Europa League.
Aside from the 2008 Intertoto Cup, Rennes have not claimed continental silverware at all, but they will travel to Italy's second city in their best form of the season.
Les Rouge et Noirs are set to meet another red-and-black side having won seven games on the spin since the New Year - if a penalty shootout success over Marseille in the Coupe de France is included - and last lost anywhere in their final Europa League group fixture two months ago.
As well as thrashing Sochaux 6-1 to book a spot in the cup quarter-finals, Rennes have beaten Nice and an improving Lyon side, in addition to edging past Montpellier and Le Havre over the past couple of weeks.
A push for European qualification is therefore under way, as Julien Stephan's arrival as head coach has helped the Breton club move to within four points of fifth-placed Lille. Since replacing Bruno Genesio, Stephan has won 10 of 14 games in charge, and after winning three straight away fixtures in Ligue 1 for the first time in four years, Rennes now resume their Europa League campaign.
Finishing second to Villarreal by just one point in Group F - albeit well clear of Maccabi Haifa and Panathinaikos - has left them with a challenging playoff contest rather than a direct place in the last 16.
Nonetheless, back-to-back victories on their travels mean that Rennes are now seeking three successive away wins in Europe for the very first time. History, however, is not on their side: they have been beaten on all three previous visits to Italy.
AC Milan form (all competitions):
L
W
W
D
W
W
Rennes Europa League form:
W
L
W
W
W
L
Rennes form (all competitions):
W
W
W
W
W
W
Team News
Milan's defensive woes continued on Sunday, as captain Davide Calabria was withdrawn during the first half of the win over Napoli and is now set to miss time with an adductor problem.
Pierre Kalulu and Fikayo Tomori are still unavailable, but Malick Thiaw is back in the fold following a hamstring injury that had kept him sidelined for two months, while winger Samu Chukwueze has just been released from Nigeria duty.
After four games with the same starting XI, Stefano Pioli was forced to replace the suspended Tijjani Reijnders last weekend, but the Dutch midfielder could now return in place of Ismael Bennacer, who is still short of fitness since leaving the Africa Cup of Nations with an injury.
Up front, Olivier Giroud has been directly involved in 11 goals from nine Europa League knockout-stage appearances to date, and at the age of 37 years 138 days could become the fourth-oldest player to score in the competition's elimination phase.
Meanwhile, Benjamin Bourigeaud - who bagged the winner against Le Havre last time out - is top scorer for Rennes in Ligue 1, with a modest tally of six goals.
He should support Martin Terrier and Arnaud Kalimuendo in attack, while recent signings Azor Matusiwa and Alidu Seidu may be involved after being added to the visitors' Europa League squad.
Influential playmaker Enzo Le Fee and Swiss midfielder Fabian Rieder are Julien Stephan's most notable absentees.
AC Milan possible starting lineup:
Maignan; Florenzi, Gabbia, Hernandez, Jimenez; Reijnders, Adli; Pulisic, Loftus-Cheek, Leao; Giroud
Rennes possible starting lineup:
Mandanda; G. Doue, Seidu, Theate, Truffert; Bourigeaud, Matusiwa, Santamaria, D. Doue; Kalimuendo, Terrier